When I started as a laboratory immunologist more than 20 years ago, the major focus in MS research was searching for ways to turn off the destructive immune attacks. These efforts paid off as there are now immune-based therapies that can help control relapsing forms of disease for many people. While researchers continue to look for ways to improve the treatment of relapsing MS, the focus in MS research is shifting to discovering strategies that stop MS progression and repair the damage that causes disability. This has relevance to people with all types of MS, but especially people with progressive MS.
In 2005 the National MS Society made significant investments into nervous system repair and protection research – and we continue to see some promising results. People are excited by the possibility, once only a dream, that we will find a way to repair damaged myelin. This is important not only for restoring function, but many believe that re-establishing the protective myelin coating on axons will shield them from further harm. As noted neuroscientist Dr. Bruce Trapp said during his presentation, “Remyelination is the best neuroprotective strategy for MS patients.”
Dr. Trapp’s team at Cleveland Clinic and others have been doing a lot of work to advance the field of nervous system repair. They have shown that new MS lesions undergo natural repair much better than older (“chronic”) ones. They’ve also reported that the problem is not a lack of cells capable of making new myelin in these old lesions, but their inability to produce new myelin, and work is now underway to figure out what the impediment is and how to jump-start the repair process.
I was intrigued by his work looking at MS lesions that straddle two different parts of the brain – the so-called white matter and the gray matter. The team found that chronic lesions in the white matter (contains a lot of myelin and the lesions can be seen on a standard MRI scan) don’t remyelinate. But chronic lesions in the gray matter (has less myelin and the lesions cannot be seen on an MRI scan), show robust remyelination – even in people living with MS into their 70’s. This opens up opportunities to compare differences in the two regions and figure out how to make the white matter repair like the gray matter. This work is already underway, as shown by a study the Trapp team presented this week at ECTRIMS.
Related to this work, Dr. Larry Sherman and colleagues at the Oregon Health and Science University found that fragments of a molecule called hyaluronic acid (HA for short) accumulate in chronic white matter lesions and could be at least partially responsible for the stalled remyelination. They have identified an enzyme that chews up the HA into fragments and have shown that inhibitors of this enzyme promote remyelination. They are now trying to figure out exactly how this works, in hopes of developing treatments that promote remyelination.
While originally studied for their anti-inflammatory activity, increasing evidence suggests that female sex hormones might be neuroprotective and/or promote repair of myelin. I saw two very interesting presentations reporting that different estrogen-like molecules could stimulate production of new myelin. Both of these projects are being supported by the Society.
Another strategy to repair myelin in MS is to introduce new repair cells into the system via transplantation. Of note was a presentation by investigators from Milan, Italy, who used mouse skin stem cells and forced them to become myelin-making cells. As in previous studies of this type, after these cells were infused into the spinal cord, they promoted recovery in mice with the MS-like disease EAE. The team showed that these cells didn’t actually make myelin themselves, and they’re starting to identify the growth factors they release, which stimulate natural repair and also reduce inflammation. More work is needed, but this type of research gives hope that this strategy may eventually help restore lost function.
Updates on two repair therapies already being tested in human clinical trials were also presented this week. The first is called anti-LINGO. LINGO is seen in neurons and myelin-producing oligodendrocytes, and blockading this protein with anti-LINGO has been shown to promote remyelination in animal models. An investigative team from Biogen Idec reported that anti-LINGO was well tolerated in people and that no negative effects were seen in the nervous system using MRI scans. This means the company will likely keep pursuing clinical development of this promising repair candidate.
In other exciting news, investigators from the Mayo Clinic are developing an agent called rHIgM22 that has been shown to promote extensive remyelination in several different animal models of MS. This agent is now in early clinical trial testing in MS.
There was a lot of strong work presented at ECTRIMS representing progress in understanding what drives myelin destruction and nerve degeneration in MS, which are key factors underlying progressive forms of the disease. We’re not there yet, but this work holds the promise of uncovering new targets for stopping progression and stimulating repair.